Q:I have heard during at least three presentations over the course of the last year that Darvocet N100 is probably no more effective than ASA, but has more significant side effects.Is someone able to provide a reference to the studies that helped to draw this conclusion?

A: As I am certain you all know: Darvocet N 100 contains 100 mg of propoxyphene napsylate and 650 mg of acetaminophen. It is the propoxyphene that will be discussed in this response. But don’t forget the potential hepatotoxicity of acetaminophen. Six Darvocet N 100 doses in 24 hours will provide 3900 mg of acetaminophen. Lastly, I am using the words propoxyphene and dextropoxyphene interchangeably.

A.All available evidence shows that propoxyphene is no more effective an analgesic than aspirin or acetaminophen. See references 1-3.

B.Propoxyphene is not recommended for treatment of chronic pain in the elderly. It can cause confusion without significant relief of pain. See references 7, 8, 11 and 12.

C.The metabolite of propoxyphene that accumulates with diminished kidney function has CNS and cardiac toxicity. Both propoxyphene at higher than therapeutic concentrations and its metabolite have local anesthetic properties which might result in a depression of myocardial function in acute overdose. High doses of propoxyphene can also depress respiration. See references 4, 5, and 6.

D.Propoxyphene is NOT discussed in three national pain management guidelines (references 9-11). This omission is reflective of the lack of enthusiasm for the drug within the pain community. However, reference 10 points out that both propoxyphene and its metabolite accumulate with chronic dosing.

E.The American Pain Society (reference 13) describes propoxyphene as “a weak analgesic; many preparations include non-narcotic analgesics; biotransformed to potentially toxic metabolite (norpropoxyphene). Propoxyphene and metabolite accumulate with repetitive dosing, overdose complicated by convulsions.”

F.Overdose with propoxyphene can result in death in spite of the fact that it is a relatively ineffective analgesic. Convulsions may be seen in patients who overdose on the drug because of the CNS stimulant effects of the metabolite of the drug (see reference 6). Remember with meperidine overdose, one may see mixed stupor (the parent drug) and convulsions (the metabolite).

G.Remember that physicians and patients still may have confidence in the drug. When it was introduced in 1957, it was thought to be the long sought after “potent” analgesic with low, if any, addiction potential. It was enthusiastically accepted by physicians who probably found its promise more compelling than the confusing data from clinical trials. Patients may report, “ I still feel pain, but I don’t care anymore.”

References 1-12

Side effects: Remember if you are comparing side effects of aspirin and propoxyphene that aspirin has many side effects: gastropathy, renal insufficiency, decreased platelet aggregation, hypersensitivity reactions, mild CNS effects, etc. Propoxyphene is an opioid and as such, it can cause sedation, nausea and respiratory depression. Although it was not originally marketed as a controlled substance, it has been abused. Propoxyphene is a Controlled Substance. Both aspirin and propoxyphene can be fatal in overdose. As stated above, overdose from propoxyphene is complicated by the fact that one may see respiratory depression and convulsions. Same thing with meperidine: mixed stupor and convulsions.

Q: Do you know of any actual studies in conjunction with the use of Demerol (meperidine)?We will be in a quandary with trying not to use Demerol with some of the physicians unless we have actual studies.

A: Those that prefer meperidine over morphine often make the statement that meperidine has no effect on the Sphincter of Oddi. There is no evidence to support this claim. See Lee and Cundiff, Archives of Internal Medicine (1998) 158:2399.

According to the AHCPR Clinical Practice Guideline: Acute Pain Management: Operative or Medical Procedures and Trauma (AHCPR 92-0032, 1992; p. 18):

“Meperidine (Demerol), a mu opioid analgesic, is commonly used for postoperative pain control. Meperidine is commonly under dosed and administered too infrequently even by physicians aware of its pharmacokinetics (Marks and Sachar, 1973). The common postoperative meperidine order of 75 mg parenterally every 4 hours as needed often is inadequate for several reasons. Meperidine produces clinical analgesia for 2.5-3.5 hours, and a dose of 75 mg every 4 hours is equivalent to only 5-7.5 mg of morphine. Therefore, to obtain postoperative analgesia equal to that from 10 mg of morphine sulfate every 4 hours, a clinician would have to use 100-150 mg of meperidine every 3 hours. Because of its unique toxicity, meperidine is often contraindicated in patients with impaired renal function and those receiving antidepressants of the monoamine oxidase inhibitor class (Wood and Cousins, 1989). Normeperidine (6-N-desmethylmeperidine) is a toxic meperidine metabolite excreted through the kidney. In patients with normal renal function, normeperidine has a half-life of 15 to 20 hours; this time is extended greatly in elderly individuals and patients with impaired renal function. Normeperidine is a cerebral irritant that can cause effects ranging from dysphoria and irritable mood to convulsions (Kaiko, Foley, Grabinski, Heidrich, Rogers, Inturissi, and Reidenberg, 1983; Szeto, Inturrisi, Houde, Saal, Cheigh, and Reidenberg, 1977). These effects have been observed even in young, otherwise healthy patients given sufficiently high doses of normeperidine postoperatively. Therefore, meperidine should be reserved for very brief courses in otherwise healthy patients, who have demonstrated an unusual reaction (e.g., local histamine release at the infusion site) or allergic response during treatment with other opioids such as morphine or hydromorphone.”

According to the AHCPR’s Clinical Practice Guideline: Management of Cancer Pain (AHCPR 94-0592, 1994; p.50):

“Meperidine may be used for brief courses (e.g., a few days) to treat acute pain and to manage rigors (shivering) induced by medication, but it generally should be avoided in patients with cancer because of its short duration of action (2.5-3.5 hours) and its toxic metabolite, normeperidine. This metabolite accumulates, particularly when renal function is impaired, and causes CNS stimulation, which may lead to dysphoria, agitation, and seizures (Kaiko, Foley, Grabinski, et al., 1983). Therefore meperidine should not be used if continued opioid use is anticipated.”

According to the American Pain Society’s Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain (1999; p. 31):

“Normeperidine, a metabolite of meperidine, is a CNS excitotoxin that produces anxiety, tremors, myoclonus, and generalized seizures when it accumulates wit repetitive dosing (Kaiko et al., 1983). Although oral doses of meperidine have only about one-quarter of the analgesic effectiveness of similar parenteral doses, they produce just as much of this toxic metabolite. Patients with compromised renal function are particularly at risk. Naloxone does not reverse, and may even exacerbate, this hyperexcitability. For these reasons, meperidine should not be used for more than 48 hours for acute pain inpatients without renal or CNS disease, or at does greater than 600 mg/24 hours, and should not be prescribed for chronic pain. This warning is particularly pertinent when treating patients with sickle-cell disease, for whom the use of meperidine, unfortunately, remains in fashion. These patients may have renal disease and a low seizure threshold, and they are particularly at risk for normeperidine-induced seizures (Tang et al., 1980). A hyperpyrexic syndrome with delirium, which can be lethal, can occur if meperidine is given to patients taking monoamine oxidase inhibitors (Browne & Linter, 1987).”

Agency for Health Care Policy and Research: Acute Pain Management: Operative or Medical Procedure and Trauma. Clinical Practice Guideline No 1. Rockville, Md: AHCPR Publication no. 92-0032, 1992.

LINK TO MEPERIDINE REFERENCES

Q: What is the correct way to manage pain/sedation for a multitrauma patient who presents to the ER with a GCS of 8?The patient was intubated with etomidate and succinylcholine.The issue here is that the neurologic exam is essential in determining the patient's need for craniotomy.For example, given a particular set of head CT findings, a craniotomy would not need to be performed if the patient has improvement in the neurologic exam over the next hour or two.

We are having some debate over this issue.The neurosurgeons want no pain Rx or sedation administered while the ER physicians are trying to push 5 of midazolam and 5 of MS04. Anyone have a good protocol to deal with this issue? 

A: The following is a response from Dr. Dan Carr of the New England Medical Center to Dr Schurr's question about tx of the patient in the ED with a GCS of 8:

Bearing in mind that I am neither a neurosurgeon nor a trauma doc (but have spent time around both), I wonder if the question has been framed to make it appear more complex than it really is. And somewhere there must be a well-reasoned algorithm about this very question. Wasn't Paul Paris writing a book about pain control in the ER a few years ago? Did it ever get published? (I think I wrote a foreword for it.)

My answer:If a patient requires intubation in the context of significant neurological compromise after head trauma (GCS 8), then controlled ventilation is mandatory (as opposed to the special case of leaving a postoperative patient intubated briefly in the PACU without ventilator hookup until their protective upper airway reflexes return and they can be extubated). To permit adequate ventilation in this context, sedation is mandatory otherwise the patient may "buck" and render ventilatory support suboptimal. Bucking the ventilator can itself raise intracranial pressure and increase the risk of brainstem herniation. Controlled ventilation is also a part of therapy in order to avoid increased pCO2, that causes cerebral vasodilation and elevated intracranial pressure. Some people add a muscle relaxant (= curare - like paralytic agent) to a hypnotic in intubated ICU patients but if the hypnotic suffices to prevent bucking and suppress awareness, the relaxant is not necessary (didn't I see an article and/or editorial recently in NEJM that addressed this point?). Also, the danger of using a muscle relaxant is that a patient might be aware while paralyzed – very psychologically damaging!

If the patient has sufficient neurological compromise at the time of initial presentation to warrant intubation, then clearly this person is at risk for brain edema and herniation, even more so if there is a pathological intracranial process. Therapy for brain edema (high dose dexamethasone, osmotic diuretic, ventilatory support to avoid high PCO2 etc) should be initiated expectantly. (I am surprised that succinylcholine was used because this can elevate intracranial pressure transiently; a nondepolarizing muscle relaxant would have been preferable.) The decision for emergent craniotomy will be based upon intracranial pressure, which should therefore be monitored while the patient is sedated, intubated and ventilated either by a "plug" transducer that can be put in at the bedside or in the ER, or by whatever noninvasive method the institution uses (e.g., Doppler).

If the intracranial pressure rises and there is already a CT-documented pathological process such as hematoma or diffuse edema, then the presumption is that this process is progressing and the patient requires urgent craniotomy. No repeat CT would be necessary. If the institution can't provide this care then it shouldn't receive/keep trauma patients. I dispute that improvement in neurological exam "over the next hour or two" obviates the need for neurosurgical intervention because such a fluctuating course is classic for subdural hematoma, that may progress to require operation.

If the ICP is stable and/or gradually falls, and extubation is to be attempted on the basis of recovery of neurological function, I would change the sedative to a short-acting agent such as propofol, which can be titrated rapidly. Lowering the infusion rate of propofol will result in a rapid emergence towards the underlying sensorium. An early sign of lightened sensorium will be adequate spontaneous ventilation while still intubated.

If the ventilatory response is suboptimal, or if the patient has delirium, and cannot be extubated, then the propofol infusion rate can be quickly increased to promptly re-"deepen" the patient. If a prolonged interval of ventilatory support is planned before the next trial of weaning/extubation, propofol can be switched to a longer acting, less expensive agent until a day or so before the next weaning trial. So, there is little need in my view to allow oneself to be trapped in a gray zone of having to monitor clinical neurological signs in this potentially unstable patient when the management can be set up to yield more readily monitored, objective data (ICP) in a smooth fashion with less aggravation for all concerned -- including the patient.

In a way this scenario reminds me of the "pain relief for abdominal trauma" scenario, in which some would still argue for withholding analgesics because of the need to observe the evolution of the patient's physical exam. However, nowadays the decision to operate is predicated upon objective findings (abdominal CT, abdominal lavage, hematocrit, white blood count...) that are uninfluenced by analgesics. Also, ordinary clinical doses of analgesics will not mask physical signs of an intra-abdominal catastrophe.

So, we no longer advocate withholding analgesics in this setting -- although we do urge that they be titrated cautiously just in case the patient does have a catastrophic intra-abdominal process brewing (e.g., dissecting aneurysm) and is sustaining systemic blood pressure by virtue of sympathetic tone, which could be decreased by analgesics.

Final points: because morphine, like other opioids, promotes CO2 retention, thereby vasodilating intracerebral vessels and elevating intracranial pressure, it should be avoided if at all possible during the initial evaluation of a patient with cranial trauma -- until and unless controlled ventilation is initiated. Also, adding a benzodiazepine like midazolam to morphine exaggerates sedation so I wouldn't use both together in the early management of a patient with potentially unstable neurological function, until and unless there was a need for deep sedation to permit ventilation.